In the art, thiolated compounds, both those provided with free SH groups, and those with the S— atom blocked by a functional group, have the capability to decrease the rigidity of protein structures, by breaking the disulphur bonds, resulting in increasing the extensibility of the protein molecule. This result is achieved by acting both on ternary and quaternary structure, without affecting the primary and secondary ones, and therefore is reversible. This action is very well known and it is applied in two large fields, like in human therapy of bronchitis, to decrease sputum viscosity and improve bronchial and tracheal clearance both in acute and chronic bronchitis; on the other hand, it is applied by cosmetic industry to improve skin softness in subjects with wrinkles or striae. In fact, the structure of keratin, the main constituent of the skin, is rich of disulphur bonds as a result of interactions between two non contiguous molecules of cisteine, in the aminoacidic chain. Same is to be said for sputum, which constituents are rich of disulphur bonds. The breaking of the disulphur bond, by reducing the —SS— bridge to two —SH free groups, allows the protein to extend, by loosing the rigidity due to the covalent bond. On the other hand, this phenomenon is reversible, in fact the two SH free groups may further interact and form an —SS— bridge.
Esters of alcohols and organic acids are known in the art and used as skin care and nurturing for the prevention and reduction of stretch marks. They substantially act while keeping essential emollients actively softening and elasticizing. Triglycerides are esters of glycerol, that are physiologically present in the animal and vegetable tissues. Those esters are composed of organic fatty acids, with a Carbon atom chain varying between 6 to 18 Carbon atoms, they may be saturated or unsaturated, mainly mono-, di- or tri-unsaturated. The chain length and the presence of double bonds affect the melting point of the fatty acids and of their esters. The lowering of the melting point confers to these compounds a semisolid or liquid state that is useful for their emollient and humectant properties. Cholesterides are esters of cholesterol and organic fatty acids, also present in nature, mostly in fats and nervous tissues of animals. They also are used in the preparation of creams and ointments due to their emollient properties. Phytosterol esters are the correspondent in the vegetables, where the sterol components of the ingredient vegetable oil phytosterol esters are beta-sitosterol, campesterol, and stigmasterol. These components of vegetable oil phytosterol esters already are present as ingredients in cosmetics as skin care products for their emollient properties, thus they have a similar intended use to cholesterides and triglycerides. Fatty acids that enter in the composition of esters with sterols are also varying between 6 to 18 Carbon atoms, they may be saturated or unsaturated, mainly mono-, di- or tri-unsaturated fatty acids. Esters of alcohols and organic acids may be synthetic, such as isopropyl-miristate and isopropyl palmitate. Isopropyl-myristate is the ester of isopropyl alcohol and myristic acid, a saturated C-14 fatty acid: it is widely used both in cosmetic and pharmaceutical industry, also for vaginal preparations. The compositions object of the present invention contain at least a thiolated compound and an ester of organic acid which act synergistically in improving tissue elasticity in terms of increased both extensibility and elastic recovery. This feature is important to increase elasticity of the distal portion of the vagina and of the perineal tissues during the last trimester of pregnancy. Spontaneous delivery is often accompanied by lacerations of the perineal tissues due to excessive extension during the expulsive phase. Short-medium term complications are often pain, dyspareunia and urinary incontinence in 30-50% of women (Lukacz E S et al. Obst Gynecol. 2006—Olsen L O, et al Obstet. Gynecol. 1997).
The practice to episiotomy may decrease the spontaneous lacerations in terms of both rate and severity of lacerations, but it is not devoid of complications, like dyspareunia and rectal incontinence of puerperal women. According to a recent systematic evidence review, although episiotomy is performed in approximately 30-35% of vaginal birth in the United States, no statistically significant difference were reported for severe vaginal or perineal trauma, dyspareunia or urinary incontinence (ACOG Practice Bulletin. Episiotomy. Clinical Management Guidelines for Obstet. Gynecol. 2006).
Perineal massage during the last weeks of pregnancy is a practice known in the art to prepare the tissues to the increased request of extension during spontaneous delivery. Ten-fifteen minutes massage is performed during the last 6-8 weeks before delivery, mostly daily or tri-weekly. Almond oil is used as a lubricant. The usefulness of this practice is controversial: according to the literature, the practice of the perineal massage is capable to improve the extensibility of the perineal tissues, by significantly reducing the incidence of trauma requiring suturing and number of episiotomy in woman without previous vaginal birth, but no differences were seen in the incidence of 1st or 2nd degree perineal tears or 3rd to 4th degree perineal trauma compared to women not practicing the perineal massage (Beckmann M M et al. Birth 2006).
It has now been shown that compositions containing at least a thiolated compound and an ester of organic acid and appropriate excipients improve the elasticity of the skin by a synergistic action of the two components, namely the thiolated compound and the ester of organic acid. Furthermore, the regular application of compositions containing at least a thiolated compound and an ester of organic acid and appropriate excipients is capable to increase the elastic properties of the distal part of the vagina and of the perineal tissues. The compositions are preferably in form of cream, ointment, gel or lotion, and are preferably topically applied by perineal massage, to improve penetration of the ingredients deeply into the perineal tissues, and to train the vaginal and perineal muscles to the expulsive phase of delivery as well.
The compositions contain at least a thiolated compound in a proportion ranging between 0.1 to 25 wt. %, preferably from 0.5 to 15 wt. %, more preferably from 1.0 to 10%, with respect to the total weight of the composition. The thiolated compound is preferably a sulphated aminoacid, more preferably a derivative of cysteine, most preferably a salt of carboxymethyl-cysteine. According to a preferred embodiment, said sulphated amino acid is selected from: 1-methionine, 1-cysteine, 1-cystine, taurine, 4-thiazolidinecarboxylic acid, carboximethylcisteine and/or methylsulphonylmethane, or a physiologically acceptable salt thereof.
The compositions contain at least an ester of organic acid in a proportion ranging between 1 to 95 wt. %, preferably from 5 to 70 wt. %, more preferably from 10 to 45%, with respect to the total weight of the composition. The ester of organic acid is preferably an ester of glycerol or an ester of animal or vegetable sterol, such as cholesterol, or a mixture thereof.
The organic acid contains from 2 to 30 carbon atoms, preferably from 6 to 18 carbon atoms, more preferably from 12 to 18 carbon atoms. The organic acid is saturated or unsaturated.
The compositions will be prepared according to conventional techniques, and may include compatible excipients and pharmaceutically acceptable carriers, e.g. ionizing agents, antioxidant agents, chelating agents, moisturizing agents, decongestant agents, disinfectant and/or antimicrobial agents, flavoring and colorants.
The compositions may also contain, in combination, other active principles with complementary or, in any case, useful activity. Examples of these compositions prepared according to the present invention include: cream, ointment, gel, lotion or foam.
The pharmaceutical compositions and the uses of the present invention will now be more fully described by the following examples. It should, however, be noted that such examples are given by way of illustration and not of limitation.